بسم الله الرحمن الرحيم (رب أوزعني أن أشكر نعمتك التي أنعمت علي وعلي والدي وأن أعمل صالحا ترضاه00000) صدق الله العظيم صدق الله العظيم

By Ragab Abd El Salam (MD) Prof. of Cardiology

Introduction - MS Affects approximately 47 plus million Americans -Of them approximately 20% develop type II DM -The remaining 80% will be able to resist for a time by beta-cell expansion, hypertrophy & hyperplasia. -But this without pay :, the price will be a condition of hyperinsulinimia & hypermylinemia which place the patients at higher risk for hypertension & CAD.

*Metabolic syndrome –X Vs Cardiac syndrome –X: The other type of syndrome –X is cardiac: it is described as : The other type of syndrome –X is cardiac: it is described as : - Typical Anginal pain - Typical Anginal pain - Positive ETT - Positive ETT - Normal coronary angiography - Normal coronary angiography Metabolic syndrome –X is usualy associated with cardiac syndrome –X, while the reverse is not the case Metabolic syndrome –X is usualy associated with cardiac syndrome –X, while the reverse is not the case In some instances both syndromes are coincident In some instances both syndromes are coincident

We try to live this day to die in another day:We try to live this day to die in another day:  Due to improved treatment of complication associated with HTN & CAD, more patients with this trio now live long enough for the clinical syndrome of heart failure.  Due to improved treatment of complication associated with HTN & CAD, more patients with this trio now live long enough for the clinical syndrome of heart failure.  Currently, we are at an intersection (crossroads) of the decreasing mortality curve from CAD-CHD and the increasing mortality curve from CHF  Currently, we are at an intersection (crossroads) of the decreasing mortality curve from CAD-CHD and the increasing mortality curve from CHF

What is the metabolic syndrome? It is characterized by a group of risk factors in one person 1-Central obesity 2-Atherogenic dyslipidemia 3-Raised blood pressure 4-Insulin resistance 5-Prothrombetic sate 6-Proinflamatory state.

The underlying causes are: 1-Overweight/obesity 1-Overweight/obesity 2-Physical inactivity 2-Physical inactivity 3-Genetic factors 3-Genetic factors

People with MS are at increased risk of: 1-CAD 1-CAD 2-CHF 2-CHF 3-Type 2 DM, 3-Type 2 DM, 4-HPN, 4-HPN, 5-Cardiomyopathy. 5-Cardiomyopathy. 6-Other diseases related to plaque buildups in artery walls (e.g: stroke & peripheral VD) 6-Other diseases related to plaque buildups in artery walls (e.g: stroke & peripheral VD)

Who has MS ? 1-It is closely associated with insulin resistance 2-genetically predisposed people to insulin resistance 3-Acquired factors : -excess body fat -excess body fat -physical inactivity -physical inactivity -central obesity -central obesity NB:-any patient with family history of type 2 DM shuod be evaluated for glucose intolerance & blood pressure abnormalities.

*Obesity & metabolic syndrome: It is directly related to MS & T2DM.It is directly related to MS & T2DM. It is important to single out obesity as it plays an important role in the development of HTN,CAD, & CHF;It is important to single out obesity as it plays an important role in the development of HTN,CAD, & CHF; Ther is a graded increase in the risk of CHF across categories of body mass index.Ther is a graded increase in the risk of CHF across categories of body mass index. For each increment of 1 inch in the BMI there will an increase in CHF of 5% for men & 7% for womenFor each increment of 1 inch in the BMI there will an increase in CHF of 5% for men & 7% for women

*Obesity increases the prevalence of most of cardiovascular risk factors *Moreover obesity shifts the manifestation of these risk factors to younger age groups such that cardiac events become clinically overt prematurely. *Moreover obesity shifts the manifestation of these risk factors to younger age groups such that cardiac events become clinically overt prematurely. * For all of these we may find in the near future that the prevalence & incidence of cardiovascular events may be increasing in a younger age population. * For all of these we may find in the near future that the prevalence & incidence of cardiovascular events may be increasing in a younger age population.

Insulin Resistance (IR) IR describes the condition whereby there is a resistance to insulin- mediated glucose uptake by cells is central to clustering of metabolic abnormalities.

Hyperglycemia IGT,IFG & T 2 DM hypertension microalbum& hyperurimia IR Obesity & dyslipidemia IR Hyperinsulinemia AMYLIN

*Clinical link of IS & MS 1-strong family history of DM. 1-strong family history of DM. 2-High risk ethnic background 2-High risk ethnic background 3-Obesity 3-Obesity 4-Macrosomia 4-Macrosomia 5-Multiparity 5-Multiparity 6-Gastational DM 6-Gastational DM 7-Polysystic ovary syndrome 7-Polysystic ovary syndrome 8-Impaired glucose intolerance 8-Impaired glucose intolerance 9-Impaired fasting glucose 9-Impaired fasting glucose 10-Aging 11-Hypertenson 10-Aging 11-Hypertenson 12-Dyslipidemia 12-Dyslipidemia

 Looking at the “whole forest” instead of looking at individual trees:  This is a global MS approach of cardiovascular risk assessment & it is important to treat the whole disease not an individual factor.  This true as each component of MS plays a role in CAD & also in the future development of cardiovascular events.

*Redox Homeostasis: -It the process of reduction & oxidation in order to re-pair unstable,damaging,reduced reactive oxygen species(ROS) which will include: OFR( superoxide & -OH-hydroxyl radical), hydrogen peroxide& reactive nitrogen species. -This is the homeostasis balance between (ROS) & antioxidant capacity

*endothelial Nitric Oxide (eNO) The protective role of eNO 1-promotes vasodilatation 2-Counteract smooth muscle cell proliferation 3-Decrease the adhesiveness to WBCs 4-decreases platelets adhesivness 5-anti-iflammatory6=anti-oxidant7-anti-fibrotic

Pathophysiology: (I) The A-FLIGHT multiple metabolic toxisties: -It is the acronym of the toxic trio of MS -this results in an elevated tension of redox stress oxygen species(ROS)& activation of remodeling pathways in the cells & tissues. -It is the acronym of the toxic trio of MS -this results in an elevated tension of redox stress oxygen species(ROS)& activation of remodeling pathways in the cells & tissues. -Each of the metabolic toxicities play s a role in the pathogenesis prior the diagnosis of overt DM. -Each of the metabolic toxicities play s a role in the pathogenesis prior the diagnosis of overt DM.

The A-FLIGHT toxicities: A -Amylin -Angiotensin II -Advanced glycation end product -Advanced lipoxidation end product -Absnce of antioxidant netwark -Aging -Atherosclerotic nephropathy

F =Free fatty acid toxicity L=lipotoxicity lipid triad: -FFA lipid triad: -FFA -ALE -ALE -Long chain acyl-COA -Long chain acyl-COA I= Insulin toxicity Insulin resistance Insulin resistance Insulin defienicy Insulin defienicy Inflammatory toxicity Inflammatory toxicity

G= G lucotoxicity H= Hypeertension toxicity Homocysteine toxicity Homocysteine toxicity T= Triglyceride toxicity Thrombotictoxicity Thrombotictoxicity Taurine(antioxidant) Taurine(antioxidant) depletion depletion

*Pathophysiologic Consequence 1-Excess (ROS) production 2- Inflammation begets inflammation 3- Cytotoxicity 4-Apoptosis 5-Atheroembolization

6-Ischemia / injury 6-Ischemia / injury 7-remodeling, systolic & diastolic dysfunction 7-remodeling, systolic & diastolic dysfunction 8-decreased nitrous oxide (NO) 8-decreased nitrous oxide (NO) 9 -Endothelial cell injury 9 -Endothelial cell injury 10 -ROS begets ROS 11-Islets of Amyloid polypeptide deposition

(II) Redox stress: Redox imbalance –a contraction of reduction & oxidation: implies of loss of redox homeostasis resulting in an excess production of (ROS) via the process of reduction or oxidation. (III) Oxidative stress: I I I Implies loss of redox homeostasis with an increase in (ROS) via sigular process of oxidation.

Origins of (ROS ) 1 -Excess oxygen ( oxygen therapy) 1 -Excess oxygen ( oxygen therapy) 2 -Absorption of radiant energy 2 -Absorption of radiant energy 3 -exosure to toxins 3 -exosure to toxins 4 -Reduction-oxidation of normals 4 -Reduction-oxidation of normals 5 -Ischemia-ischemia reperfusion inury 5 -Ischemia-ischemia reperfusion inury 6 -Inflammatory processes. 6 -Inflammatory processes. 7 -Autocatalytic reaction(ROS beget ROS) 7 -Autocatalytic reaction(ROS beget ROS)

*Role of (ROS): -elevated tension of redox stress. -tremendous local energy production -this will lead to damage of the surroundings -consume NO ONOO which also consumes & inactivate NO NB:It was known for a time that (ROS) are toxic via A) lipid peroxidation B) DNA damage leading to mutation& death ( apoptosis) C) Cross-linkage to stiff aged proteins -

“A thief in the night  I t points to Homocysteine: -As it consumes the endogenous antioxidant NO”& the antioxidant enzymes. -Not only ” a rubber “but also Hcy acts as an accelerant to a fire where the fire is ROS & redox stress -In addition to his Hcy allows other A-FLIGHT toxicities to take a greater toll & overwhelm the endogenous antioxidant mechanisms within myocardium..

How is the metabolic syndrome diagnosed? The metabolic syndrome is diagnosed by the presence of three or more of the following : The metabolic syndrome is diagnosed by the presence of three or more of the following : 1- Central obesity(as measured by waist circumferance) 1- Central obesity(as measured by waist circumferance) -Men—greater than 40 inches -Men—greater than 40 inches -Women—greater than 35 inches -Women—greater than 35 inches 2-FB Triglyc. is more than 150 mg/dl 2-FB Triglyc. is more than 150 mg/dl 3-Blood HDL: 3-Blood HDL: -Men-less than 40 mg/dl -Men-less than 40 mg/dl -Women –less than 50mg/dl -Women –less than 50mg/dl

4-Blood pressure is equal to or greater than 130/85 mmHg 5-fasting blood glucose is equal to or greater than 110 mg/dl This diagnostic criteria are according to the Adult Treatment Panel- III (ATP) NB: ATP-III did not find evidence to recommend routine assessment of insulin resistance ( e.g. increased fasting insulin level),pro-thrombotic states & pro-inflammatory state

MS & Cardiomyopathy: Mechanisms: 1- Basement membrane thickening 1- Basement membrane thickening 2- Fibrosis (perivascular & interstitial) 2- Fibrosis (perivascular & interstitial) 3- PAS+hyaline staining of interstitium 3- PAS+hyaline staining of interstitium 4- Decreased Capillary density & capillary microangiopathy. 4- Decreased Capillary density & capillary microangiopathy. 5- Endothelial cell proliferation 5- Endothelial cell proliferation 6- Myocardial-myocyte hypertrophy(Myocytolysis) 6- Myocardial-myocyte hypertrophy(Myocytolysis) 7- Accelerated atherosclerosis(atheroscleropathy) 7- Accelerated atherosclerosis(atheroscleropathy) 8- Microangiopathy. 8- Microangiopathy.

The trigger trios in MS includes: 1- th e multiple metabolic A-FLIGHT toxicities 1- th e multiple metabolic A-FLIGHT toxicities 2-elevated tension of redox stress 2-elevated tension of redox stress 3-Nitric oxide inhibition 3-Nitric oxide inhibition 4- Vascular paradox: Accelerated Angiogenesis( capillary vessel formation) & impaired arteriogenesis( collateral vessels formation) 4- Vascular paradox: Accelerated Angiogenesis( capillary vessel formation) & impaired arteriogenesis( collateral vessels formation) 5-Elevated plasminogen activator inhibitor- 1(PA1-1) so, there is not only impaired fibrinolysis but also impaired remodeling & collateralization. 5-Elevated plasminogen activator inhibitor- 1(PA1-1) so, there is not only impaired fibrinolysis but also impaired remodeling & collateralization.

Atherosclerosis & MS: Atherosclerosis is accelerated in MS along several mechanisms: 1-Endothelial dysfunction with decreaese in NO 2-Metabolic A-FLIGHT toxicities 3-ROS with its bad effects 4-Homocysteine ( a theif in the night. 5-The eNOS gene, enzyme & eNOS reaction: -defect in the eNOS gene is associated with insulin resistance, hypertension & dyslipidemia. -defect in the eNOS gene is associated with insulin resistance, hypertension & dyslipidemia. -The Glu-Asp gene polymorphism: -The Glu-Asp gene polymorphism:

It is associated with increased incidence hypertension & spastic angina It is associated with increased incidence hypertension & spastic angina *Higher frequency of abnormal angiographic findings *Significant decrease in basal NO production * Not only this, but also this gene could iteract with other gene polymorphism and special environmental conditions as(smoking, obesity, & the A-FLIGHT toxicities of MS)

MS & Remodeling: It is defined as any change in an existence or native structure. It is defined as any change in an existence or native structure. - The trigger may be tear-down or degrade the existence - The trigger may be tear-down or degrade the existence -The matrix metalloproeinases(MMPs) are the degrading enzymes responsible for degradation of the existence structures -The matrix metalloproeinases(MMPs) are the degrading enzymes responsible for degradation of the existence structures - Normally these enzymes are present in an inactive latent zymogen ( proMMPs) - Normally these enzymes are present in an inactive latent zymogen ( proMMPs)

Types of Remodeling: A) Passive remodeling : occurs at the local site of ischemia & is related to myocyte necrosis & is also termed surragate fibrosis. B) Active remodeling: occurs at a site remote of injury or ischemia in non- infarcted area & is not associated with myocyte nerosis& also termed interstitial fibrosis

MMPs are activated in MS by several factors : e.g. ROS & plasminAdvanced glycation end products(AGE) - once MMPs are activated degradation of collagen starts first, followed by elastin & then stiffer matrix occurs with myocardial remodeling (decreasing vent. compliance, relaxation & filling).

MS & Diastolic Dysfunction(Dd): - It may be observed in about of 40 % of cases free of CAD & other factors cause Dd - It may be observed in about of 40 % of cases free of CAD & other factors cause Dd - The global systolic function is usually normal. - The global systolic function is usually normal. - Other associated factors of MS increases the incidence of Dd in this syndrome. - Other associated factors of MS increases the incidence of Dd in this syndrome.

* Mechanisms of Dd in MS: 1-Marked increased interstitial & perivascular fibrosis of ECM. 2-The presence of a concederable amount of Periodic Acid Schiff positive material( in the interstitium, arterial wall & basement membrane.) 3-Myocardial remodeling. 4-Redox stress & injury-response to injury 5-Myocyte hypertrophy & excessive collagen deposition with fibrosis.

6-Activation of Renin-Angiotensin-Aldosteron system. *All these changes will lead to decrease in compliance & impaired relaxation as a result of gradual disruption of the myofibrillar architecture, whereby the ventricle loses its ability to return to its normal resting state during diastole resulting impaired filling.

Treatment of metabolic syndrome: (I) Insulin resistance: (I) Insulin resistance: -T here is no definite drug treatment for this. -T here is no definite drug treatment for this. - B ut the safest & most effective way is to reduce insulin resistance is weight loss & increased physical activity. - B ut the safest & most effective way is to reduce insulin resistance is weight loss & increased physical activity. - C arefully choose antihypertesive drugs because different agents have different effects on insulin resistance. - C arefully choose antihypertesive drugs because different agents have different effects on insulin resistance.

(II) Aggressive treatment of each individual metabolic disorder associated with MS : =Dyslipidemia =Dyslipidemia =Hypertension =Hypertension = Clotting disorder = Clotting disorder =Hyperglycemia or DM =Hyperglycemia or DM These individual factors should be agressively treated according to the standard guidelnes.

The RAAS acronym : for prevention & treatment: The RAAS acronym : for prevention & treatment: R= Reductase Inhibitor (HMG-CoA) A= ACEI—prils,, ARBS-sartans Adrenergic (blockade) of prorenin Adrenergic (blockade) of prorenin A= Aggressive control of diabetes Aggressive control of hypertension Aggressive control of hypertension Aggressive control of homocysteine Aggressive control of homocysteine S= Statins

*RAAS is a multifactorial & global approach to prevent & slow the progression of islet, intimal, renal neoronal,retinal & myocardial redox stress which is directly implicated in the development of multiple MS & diabetic-opathies & the vascular end stage on myocardium.

By using aggressive reducing the elevated substrates producing the A-FLIGHT toxicities & ROS & using the simple RAAS acronym we my be able to restore endogenous antioxidant & antioxidant network specially eNO.

(IV) lowering the levels of (PAI-I): -Allow the myocardiumto be able to undergo remodling, collateralization arteriogenesis with collateral vessels formation -Allow the myocardiumto be able to undergo remodling, collateralization arteriogenesis with collateral vessels formation - Contribute in awakening of hibernating myocardium & improve myocardial function. - Contribute in awakening of hibernating myocardium & improve myocardial function. This can be achieved by MMP-Inhibitor & Antioxidant This can be achieved by MMP-Inhibitor & Antioxidant

(V) Ineresting point: The commonally used antibiotic (Tetracycline) has a unique action on MMPs independent of their antibiotic action. It inhibits MMPs activity. So this antibiotic may be introduced to ameliorate myocardial nitric oxide dysfunction.

(V) Treatment paradigm for Endothelial dysfunction : 1-Prevent the competitive inhibition by ADMA(Asymmetric Dimethylarginine 2-prevent hs-CRP from decreasing eNOS & prevent glycation of eNOS enzyme 3-Add folic acid to lower Homocysteine & ADMA levels as well as restoring BH2 & BH3.

We are awaiting the availability of new MMP-inhibitors,& new antioxidantsmolecules such as : - SOD & catalase mimetics - SOD & catalase mimetics - New probucole –like (phenolic - New probucole –like (phenolic analog)AGI-1067 analog)AGI-1067

Recently the use of : - Thiazolodinedions - Thiazolodinedions - Statins - Statins - ACE-inhibitors - ACE-inhibitors - ATI-blokers - ATI-blokers  Is a strongly suggested,because they are effective “causal antioxidants”  Is a strongly suggested,because they are effective “causal antioxidants”

The Empower of RAAS a t an earliar stage in the treatment of the paradigm people may be able to live a longer life with less a t an earliar stage in the treatment of the paradigm people may be able to live a longer life with less morbidity, mortality & live to die another day……. morbidity, mortality & live to die another day…….

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